The central hypothesis of this proposal is that the suppression of GnRH neuronal activity during lactation is due to neural impulses, derived from the suckling stimulus, that alter hypothalamic function and to the change in energy balance associated with milk production. We have identified specific areas in the brainstem that are activated by the suckling stimulus; neurons from each of these areas send projections to the arcuate nucleus of the hypothalamus. We also reported that several neuronal systems in the arcuate nucleus are altered during lactation (increased NPY and AGRP, decreased POMC). These changes are consistent with the chronic hyperphagia of lactation. Our studies showed that NPY projections from the arcuate nucleus makes direct contact with GnRH neurons in the preoptic area and with CRH neurons in the periventricular nucleus (a key site for regulation of food intake). Also, NPY receptors (Y5 subtype) are expressed on GnRH and CRH neurons. Thus, we have established the neuroanatomic framework by which increased NPY activity in the arcuate nucleus could serve as a key element in linking changes in energy balance to the suppression of GnRH neuronal activity during lactation. Another indicator of the change in energy balance is the suppression of leptin during lactation in association with milk production. The proposed experiments expand on these findings and will use three approaches: 1) Neuroanatomical studies will determine the phenotypes of the suckling-activated brainstem neurons that make contact with NPY or POMC neurons in the arcuate nucleus and with GnRH neurons in the preoptic area. 2) Physiological studies will determine if the increase in NPY and the decrease in leptin play functional roles in the suppression of GnRH neuronal activity. 3) Functional genomics will be used to identify additional relevant genes that play key roles in the regulation of NPY and GnRH neurons and in conveying information about the state of energy balance during lactation. The interaction between reproductive function and energy balance during lactation provides a physiological model for studying a number of conditions in women (under-nutrition, anorexia nervosa, bulimia and exercise-induced amenorrhea) that involve a suppression of reproductive function associated with changes in energy balance. All of these conditions have common mechanisms underlying the decrease in GnRH activity.